高表达PSMD11促进胃癌细胞上皮-间质转化进程并影响患者预后

doi:10.12122/j.issn.1673-4254.2025.12.22

摘要/Abstract

摘要：

目的探究26S蛋白酶体非ATP酶调节亚基11（PSMD11）在胃癌中的表达情况及其对患者远期预后价值。方法纳入我院2016年1月~2019年12月94例胃癌患者，通过免疫组化检测胃癌及癌旁组织中PSMD11、Ki67的表达水平，分析其与患者临床病理参数及术后5年生存情况的关系。通过GEPIA和UALCAN数据库分析PSMD11在胃癌中的表达情况，利用KM-plotter数据库预测其预后5年生存率。采用KEGG和GO富集分析预测PSMD11的生物学功能及潜在机制，构建PSMD11敲低和过表达的HGC-27细胞模型，采用划痕愈合实验、Transwell实验评估胃癌细胞迁移侵袭能力，Western blotting检测上皮-间质转化（EMT）标志物及TGF-β/Smad通路关键分子表达水平。结果数据库联合分析显示PSMD11在胃癌中高表达，且与Ki67表达呈正相关（r=0.73，P<0.05）。KM-plotter数据库及本院患者临床数据生存分析显示，PSMD11高表达与胃癌预后较差呈正相关，并经单因素、多因素Cox回归分析显示，PSMD11为影响胃癌患者预后的独立危险因素（HR：2.167，95% CI：1.159~4.051，P=0.015）。富集分析结果提示PSMD11与胃癌EMT进程和TGF-β信号通路相关。细胞划痕和Transwell实验结果显示，上调PSMD11后HGC-27细胞的迁移和侵袭能力增强，下调PSMD11则减弱（P<0.05）。Western blotting结果显示，上调PSMD11可增加Vimentin、N-cadherin、TGF-β和p-Smad2/3的表达水平，减少E-cadherin的表达，下调PSMD11则相反（P<0.05）。结论 PSMD11在胃癌中高表达并影响患者预后，其可能通过激活TGF-β/Smad信号通路来驱动胃癌细胞EMT进程。

关键词: PSMD11, 胃癌, 预后, 上皮-间质转化, TGF-β/Smad

Abstract:

Objective To investigate the expression of the 26S proteasome non-ATPase regulatory subunit 11 (PSMD11) in gastric cancer and its impact on long-term patient prognosis. Methods Tumor and adjacent tissue samples were collected from a cohort of 94 gastric cancer patients treated at our hospital from January, 2016 to December, 2019. Immunohistochemistry was used to detect PSMD11 and Ki67 expression levels in the tissues, whose correlations with clinicopathological parameters and postoperative 5-year survival of the patients were analyzed. PSMD11 expression in gastric cancer was also analyzed using data from the GEPIA and UALCAN databases, while the KM-plotter database was used to predict 5-year survival rates. KEGG and GO enrichment analyses were employed to predict the biological functions and mechanisms of PSMD11. In cultured HGC-27 cells, the effects of PSMD11 knockdown and overexpression on cell migration, invasion and expressions of epithelial-mesenchymal transition (EMT) markers and TGF‑β/Smad pathway proteins were evaluated using scratch wound healing assay, Transwell assay, and Western blotting. Results Bioinformatic analysis showed that PSMD11 expression was significantly elevated in gastric cancer and positively correlated with Ki67 expression (r=0.73, P<0.05). Survival analysis suggested that high PSMD11 expression was correlated with a poorer prognosis in gastric cancer patients. Univariate and multivariate Cox regression analyses identified PSMD11 as an independent prognostic risk factor in gastric cancer (HR: 2.167, 95% CI: 1.159-4.051, P=0.015). Enrichment analysis suggested involvement of PSMD11 in EMT and TGF‑β signaling. In HGC-27 cells, PSMD11 overexpression significantly enhanced while PSMD11 knockdown suppressed cell migration and invasion. PSMD11 overexpression significantly increased the expression levels of vimentin, N-cadherin, TGF‑β, and p-Smad2/3 and reduced E-cadherin expression, and PSMD11 knockdown produced the opposite changes. Conclusion PSMD11 is overexpressed in gastric cancer and adversely affects patient prognosis likely by driving EMT via activation of the TGF-β/Smad signaling pathway.

Key words: PSMD11, gastric carcinoma, prognosis, epithelial-mesenchymal transition, TGF-β/Smad pathway

周仁杰, 杨晶晶, 宋博文, 陈孝华, 王炼, 王月月, 左芦根, 朱冰. 高表达PSMD11促进胃癌细胞上皮-间质转化进程并影响患者预后[J]. 南方医科大学学报, 2025, 45(12): 2747-2755.

Renjie ZHOU, Jingjing YANG, Bowen SONG, Xiaohua CHEN, Lian WANG, Yueyue WANG, Lugen ZUO, Bing ZHU. PSMD11 overexpression promotes epithelial-mesenchymal transition in gastric cancer and affects patient prognosis[J]. Journal of Southern Medical University, 2025, 45(12): 2747-2755.

图/表 10

图1 胃癌组织中PSMD11和Ki67的表达及相关性分析

Fig.1 Expressions and correlation analysis of PSMD11 and Ki67 in gastric cancer tissues. A: Expression of PSMD11 in pan-cancer. B, C: Expression of PSMD11 in gastric cancer and adjacent tissues. D: Immunohistochemical staining of PSMD11 and Ki67. E, F: Relative IOD values of PSMD11 and Ki67. G: Correlation between PSMD11 and Ki67. *P<0.05, **P<0.01, ***P<0.001 vs Normal/Adjacent group.

图2 胃癌组织中PSMD11的表达与临床病理学参数的关系

Fig.2 Relationship between PSMD11 expression in gastric cancer tissues and clinicopathological parameters of the patients. A, B: Correlation of PSMD11 expression levels with tumor grades and stages. C: Correlation of PSMD11 expression level with lymph node metastasis of gastric cancer. *P<0.05, ***P<0.001 vs adjacent tissue.

表1 胃癌组织中PSMD11表达水平与胃癌恶性进展参数的关系

Tab.1 Relationship between PSMD11 expression level in gastric cancer tissues and parameters of malignant progression in gastric cancer patients (n, %)

Characteristics	n	PSMD11 expression (n=47)		χ²	P
Characteristics	n	Low	High	χ²	P
Gender				0.048	0.826
Female	31	15 (48.39%)	16 (51.61%)
Male	63	32 (50.79%)	31 (49.21%)
Age (year)				0.048	0.826
<60	31	16 (51.61%)	15 (48.39%)
≥60	63	31 (49.21%)	32 (50.79%)
Pathohistological type				0.052	0.82
Adenocarcinoma	67	34 (50.75%)	33 (49.25%)
Other	27	13 (48.15%)	14 (51.85%)
CEA (μg/L)				13.155	<0.001
<5	35	26 (74.29%)	9 (25.71%)
≥5	59	21 (35.59%)	38 (64.41%)
CA19-9 (kU/L)				10.938	0.001
<37	44	30 (68.18%)	14 (31.82%)
≥37	50	17 (34%)	33 (66%)
Tumor size (cm)				1.549	0.213
<5	42	24 (57.14%)	18 (42.86%)
≥5	52	23 (44.23%)	29 (55.77%)
Histological Grading				4.257	0.039
G1-G2	46	28 (60.87%)	18 (39.13%)
G3-G4	48	19 (39.58%)	29 (60.42%)
T Stage				11.525	0.001
T1-T2	36	26 (72.22%)	10 (27.78%)
T3-T4	58	21 (36.21%)	37 (63.79%)
N Stage				11.141	0.001
N0-N1	40	28 (70%)	12 (30%)
N2-N3	54	19 (35.19%)	35 (64.81%)

图3 PSMD11对胃癌患者预后的影响

Fig.3 Effect of PSMD11 on prognosis of patients with gastric cancer. A: Kaplan-Meier analysis. B: Survival curves. C: Predictive value of PSMD11 for 5-year postoperative survival in gastric cancer patients.

图4 胃癌患者术后5年生存情况的单因素分析及多因素Cox回归

Fig.4 Univariate analysis and multifactorial Cox regression of survival of gastric cancer patients within 5 years after surgery.

图5 PSMD11与胃癌共表达基因的KEGG和GO富集分析

Fig.5 KEGG and GO enrichment analyses of PSMD11 and gastric cancer co-expressed genes. A: KEGG enrichment analysis results. B: GO enrichment analysis results.

图6 PSMD11促进胃癌细胞的迁移和侵袭(Transwell实验)

Fig.6 PSMD11 overexpression promotes migration and invasion of gastric cancer cells (Transwell assay). A-C: Lentivirus-mediated knockdown and overexpression of PSMD11 in HGC-27 cells. D-I: Migration and invasion of the transfected HGC-27 cells (n=3), Si: siRNA; LV: Overexpression. *P<0.05 vs Si-NC or LV-Control.

图7 PSMD11促进胃癌细胞的迁移和侵袭(划痕实验)

Fig.7 Wound healing assay showing that PSMD11 overexpression promotes migration and invasion of gastric cancer cells. A-C: PSMD11 overexpression promotes HGC-27 cell migration in Wound-Healing assay. n=3, Si: siRNA; LV: overexpression. *P<0.05 vs Si-NC or LV-Control.

图8 PSMD11促进胃癌细胞的EMT进程

Fig.8 PSMD11 promotes EMT process in gastric cancer cells. A-C: Expressions of key proteins of EMT in gastric cancer cells (n=3). Si: siRNA. *P<0.05 vs Si-NC or LV-Control.

图9 PSMD11高表达激活TGF-β/Smad信号通路

Fig.9 Overexpression of PSMD11 in gastric cancer activates the TGF-β/Smad signaling pathway. A-C: Expressions of TGF-β1, p-Smad2/3, and Smad2/3 in HGC-27 cells. *P<0.05 vs Si-NC or LV-Control.

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